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Blood, 15 May 2004, Vol. 103, No. 10, pp. 3669-3676. Prepublished online as a Blood First Edition Paper on January 15, 2004; DOI 10.1182/blood-2003-11-3775. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-11-3775v1 103/10/3669    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Smith, B. D. Articles by Small, D. Search for Related Content PubMed PubMed Citation Articles by Smith, B. D. Articles by Small, D. Related Collections Oncogenes and Tumor Suppressors Signal Transduction Clinical Trials and Observations Neoplasia Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia B. Douglas Smith, Mark Levis, Miloslav Beran, Francis Giles, Hagop Kantarjian, Karin Berg, Kathleen M. Murphy, Tianna Dauses, Jeffrey Allebach, and Donald Small From the Departments of Oncology, Pediatrics, and Pathology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; and the Department of Oncology, M. D. Anderson Cancer Center, Houston, TX. Activating mutations of FMS-like tyrosine kinase 3 (FLT3) are present in approximately 30% of patients with de novo acute myeloid leukemia (AML) and are associated with lower cure rates from standard chemotherapy-based treatment. Targeting the mutation by inhibiting the tyrosine kinase activity of FLT3 is cytotoxic to cell lines and primary AML cells harboring FLT3 mutations. Successful FLT3 inhibition can also improve survival in mouse models of FLT3-activated leukemia. CEP-701 is an orally available, novel, receptor tyrosine kinase inhibitor that selectively inhibits FLT3 autophosphorylation. We undertook a phase 1/2 trial to determine the in vivo hematologic effects of single-agent CEP-701 as salvage treatment for patients with refractory, relapsed, or poor-risk AML expressing FLT3-activating mutations. Fourteen heavily pretreated AML patients were treated with CEP-701 at an initial dose of 60 mg orally twice daily. CEP-701–related toxicities were minimal. Five patients had clinical evidence of biologic activity and measurable clinical response, including significant reductions in bone marrow and peripheral blood blasts. Laboratory data confirmed that clinical responses correlated with sustained FLT3 inhibition to CEP-701. Our results show that FLT3 inhibition is associated with clinical activity in AML patients harboring FLT3-activating mutations and indicate that CEP-701 holds promise as a novel, molecularly targeted therapy for this disease. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Pharmacodynamics provide critical insight in drug development Michael Grever Blood 2004 103: 3614. [Full Text] [PDF] This article has been cited by other articles: M. H. Chen, R. Kerkela, and T. Force Mechanisms of Cardiac Dysfunction Associated With Tyrosine Kinase Inhibitor Cancer Therapeutics Circulation, July 1, 2008; 118(1): 84 - 95. [Full Text] [PDF] R. C. 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Estey Statistical Considerations in Trials of Targeted Therapy: Acute Myelogenous Leukemia as an Example Am. Assoc. Cancer Res. Educ. Book, April 1, 2006; 2006(1): 289 - 292. [Full Text] [PDF] H. S. Radomska, D. S. Basseres, R. Zheng, P. Zhang, T. Dayaram, Y. Yamamoto, D. W. Sternberg, N. Lokker, N. A. Giese, S. K. Bohlander, et al. Block of C/EBP{alpha} function by phosphorylation in acute myeloid leukemia with FLT3 activating mutations J. Exp. Med., February 21, 2006; 203(2): 371 - 381. [Abstract] [Full Text] [PDF] C. D. Baldus, C. Thiede, S. Soucek, C. D. Bloomfield, E. Thiel, and G. Ehninger BAALC Expression and FLT3 Internal Tandem Duplication Mutations in Acute Myeloid Leukemia Patients With Normal Cytogenetics: Prognostic Implications J. Clin. Oncol., February 10, 2006; 24(5): 790 - 797. [Abstract] [Full Text] [PDF] D. Small FLT3 Mutations: Biology and Treatment Hematology, January 1, 2006; 2006(1): 178 - 184. [Abstract] [Full Text] [PDF] F. Heidel, F. K. Solem, F. Breitenbuecher, D. B. Lipka, S. Kasper, M. H. Thiede, C. Brandts, H. Serve, J. Roesel, F. Giles, et al. Clinical resistance to the kinase inhibitor PKC412 in acute myeloid leukemia by mutation of Asn-676 in the FLT3 tyrosine kinase domain Blood,